A physical and chemical comparison of material from a conventional spray-dried system and a single particle spray-dried system.

When assessing the suitability of potential drug/polymer systems for improving drug bioavailability, substantial efficiency gains can be achieved through the development and application of rapid miniaturised screening methods. For this to be possible new methods of small-scale formulation manufacture that produce materials equivalent to full-scale manufacture are urgently required. In this work, we use Atomic Force Microscopy (AFM) and Confocal Raman Microscopy (CRM) to investigate the potential physical and chemical equivalence of individually dried particles generated using a DRYING KINETICS ANALYZER™ (DKA) with material from a conventional spray-drier. For our model system of griseofulvin (at loadings of 2.5%, w/w and 20%, w/w) and PEG 6000, the results demonstrate physicochemical equivalence between the two spray-drying methods for the same drug loading. Thus we suggest that single particle spray drying offers a viable and novel route to the production of materials for miniaturised methods of screening candidate drug/polymer formulations.

The stability of solid dispersions of felodipine in polyvinylpyrrolidone characterized by nanothermal analysis.

Nanothermal analysis (NTA) supported by atomic force microscopy imaging has been used to study the changes that occur at the surfaces of solid dispersions of the drug felodipine and the water soluble polymer, polyvinylpyrrolidone (PVP) on exposure to standard pharmaceutical environmental stress conditions. Exposure to relative humidities above 75% (at 40 °C) was sufficient to achieve phase separation of the drug and polymer into areas which displayed a glass transition temperature consistent with pure drug and polymer over a period of a few days. Higher values of humidity at 25 °C (e.g. 95%RH) were also sufficient to cause such phase separation within a day. Extended studies of up to two months showed an eventual crystallization of the drug. NTA is shown to be effective at the early detection of instabilities in solid dispersions and the quantifiable identification of the relative composition of phase separated domains based upon their glass transition temperatures. The combined nanoscale analytical approach employed here is able to systematically study the influence of storage conditions and different drug loadings and to evaluate physical stability as a function of environmental conditions.

Nanoscale thermal analysis of pharmaceutical solid dispersions.

Formation of a solid solution of a drug in a water-soluble polymer is one of the primary techniques used to improve the dissolution rate and thus bioavailability of a poorly water-soluble drug. Understanding and detecting the state of the drug inside such a polymer matrix is critically important since issues such as drug stability, safety and efficacy can be greatly affected. In this study, two model formulations were prepared containing low and high levels of drug content. The heterogeneity of the formulations has been investigated using a novel nanothermal analysis technique. This technique has demonstrated a promising capability for imaging and quantitatively characterising the nanoscale properties of solid dispersion formulations.

Detection of low levels of amorphous lactose using H/D exchange and FT-Raman spectroscopy.

PURPOSE: To demonstrate the potential of monitoring H/D exchange by FT-Raman spectroscopy as a tool for the detection and quantification of low levels of amorphous lactose in formulations. METHODS: Samples containing different proportions of amorphous and crystalline lactose were prepared. H/D exchange was carried out by exposing the samples to a flow of D(2)O vapour. A calibration curve was constructed from the FT-Raman spectra of the deuterated samples by integrating the nu(OD) band and normalizing to an internal standard. This method was benchmarked against a conventional approach using Raman spectroscopy where the ratio of Raman bands associated with crystalline and amorphous lactose is used to estimate the amorphous content. RESULTS: The H/D exchange method revealed a linear response over the entire composite range with an excellent correlation coefficient (R (2) = 0.999). The sensitivity of this approach in detecting the amount of amorphous lactose present in a blend is significantly greater than that offered by conventional FT-Raman in the 0-10% level of amorphous material. CONCLUSIONS: A non-destructive method that is capable of providing reproducible measurements of low levels of amorphous material in lactose has been demonstrated and this method has enhanced sensitivity relative to approaches using Raman spectroscopy without deuteration.

Characterization of antigens adsorbed to anionic PLG microparticles by XPS and TOF-SIMS.

The chemical composition of the surface of anionic PLG microparticles before and after adsorption of vaccine antigens was measured using X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (TOF-SIMS). The interfacial distributions of components will reflect underlying interactions that govern properties such as adsorption, release, and stability of proteins in microparticle vaccine delivery systems. Poly(lactide-co-glycolide) microparticles were prepared by a w/o/w emulsification method in the presence of the anionic surfactant dioctyl sodium sulfosuccinate (DSS). Ovalbumin, lysozyme, a recombinant HIV envelope glyocoprotein and a Neisseria meningitidis B protein were adsorbed to the PLG microparticles, with XPS and time-of-flight secondary mass used to analyze elemental and molecular distributions of components of the surface of lyophilized products. Protein (antigen) binding to PLG microparticles was measured directly by distinct elemental and molecular spectroscopic signatures consistent with amino acids and excipient species. The surface sensitive composition of proteins also included counter ions that support the importance of electrostatic interactions being crucial in the mechanism of adsorptions. The protein binding capacity was consistent with the available surface area and the interpretation of previous electron and atomic force microscope images strengthened by the quantification possible by XPS and the qualitative identification possible with TOF-SIMS. Protein antigens were detected and quantified on the surface of anionic PLG microparticles with varying degrees of efficiency under different adsorption conditions such as surfactant level, pH, and ionic strength. Observable changes in elemental and molecular composition suggest an efficient electrostatic interaction creating a composite surface layer that mediates antigen binding and release.

Elastic modulus measurements from individual lactose particles using atomic force microscopy.

The elastic modulus of pharmaceutical materials affects a number of pharmaceutical processes and subsequently formulation performance and is currently assessed by bulk methods, such as beam bending of compacts. Here we demonstrate the accurate measurement of the elastic modulus of alpha monohydrate lactose from the dominant (011) face of single crystals using atomic force microscopy (AFM) as 3.45+/-0.90GPa. The criteria to ensure this data is recorded within the elastic limit and can be modelled using Hertzian theory are established. We compare and contrast this AFM method to a permanent indentation technique based upon a much larger Berkovich pyramidal indenter on a lactose compact and the wider literature. Finally the AFM was utilized to study the elastic response of amorphous lactose, demonstrating that the physical state of the amorphous material changes under repeated loading and behaves in a more crystalline manner under repeated force measurements, suggesting a pressure induced phase transition. The AFM based approach demonstrated has the significant advantages of requiring minimal sample, no need for producing a compact, being non-destructive in that no permanent indent is required and providing a technique capable of detecting variations in material properties across a single particle or a number of particles.

Determination of the surface free energy of crystalline and amorphous lactose by atomic force microscopy adhesion measurement.

PURPOSE: This study was conducted to accurately measure the dispersive surface free energy of lactose solids in ordered and disordered states. METHODS: Atomic force microscopy (AFM) was used to determine the contact adhesion force between an AFM tip and lactose under low humidity (ca. 1% RH). The geometry of the tip contacting apex was characterized by scanning a porous aluminum film with ultrasharp spikes (radius 2-3 nm). A sphere vs. flat surface model was employed to relate the adhesion force determined to the surface energy based upon the Johnson-Kendal-Roberts theory. Spray-dried amorphous lactose in a compressed-disk form and single crystals of alpha-lactose monohydrate were prepared as model samples. RESULTS: The condition of the smooth sample surface and sphere-shaped tip used was shown to be appropriate to the application of the JKR model. The surface energy of crystalline [(0,-1,-1) face] and amorphous lactose was determined to be 23.3 +/- 2.3 and 57.4 +/- 7.9 mJ m(-2), respectively. CONCLUSIONS: We have demonstrated the capability of AFM to measure the dispersive surface free energy of pharmaceutical materials directly through a blank probe at the nanometer scale. These data, although consistent with results from more traditional methods, illustrate some unique attributes of this approach, namely, surface energies are directly derived from solid-solid interactions, measurements may be made on specific crystalline faces, and the potential exists to identify the submicron heterogeneity of organic solids in terms of their molecular energy states (such as ordered and disordered lactose).

Identifying and mapping surface amorphous domains.

PURPOSE: Undesirable amorphous material generation during formulation is implicated in a growing number of pharmaceutical problems. Due to the importance of interfacial properties in many drug delivery systems, it seems that surface amorphous material is particularly significant. Consequently, this study investigates a range of methods capable of detecting and mapping surface amorphous material. METHODS: A micron-sized localized surface domain of amorphous sorbitol is generated using a novel localized heating method. The domain is subsequently investigated using atomic force microscopy (AFM) imaging, nanomechanical measurements, and Raman microscopy 3-D profiling. RESULTS: AFM phase and height images reveal nanoscale-order variations within both crystalline and amorphous sorbitol domains. Nanomechanical measurements are able to quantitatively distinguish the amorphous and crystalline domains through local Young's modulus measurements. Raman microscopy also distinguishes the amorphous and crystalline sorbitol through variations in peak width. This is shown to allow mapping of the 3-D distribution of the amorphous phase and is hence complementary to the more surface sensitive AFM measurements. CONCLUSIONS: AFM and Raman microscopy map the distribution of amorphous material at the surface of a sorbitol crystal with submicron spatial resolution, demonstrating surface analysis methods for characterizing semicrystalline solids generated during pharmaceutical processing.